The soil nematode Caenorhabditis elegans (C. elegans) is an excellent model organism for investigating the process of aging. The Dillin group uses long-lived C. elegans mutants that are deficient in the electron-transport chain (ETC). When the ETC deficiency occurs only in neurons, a mitochondria-specific stress response, known as the Unfolded Protein Response in mitochondria (UPRmt) is activated in the intestine, which in turn is required to sustain the mutant's extended lifespan. Long distance coordination between neurons and the intestine of the C. elegans mutants described above implies the existence of a signaling molecule (or molecules) that the Dillin group termed mitokine. This F33 application explores the hypothesis: Mitochondrial ROS in neurons of ETC- deficient C. elegans are essential for mitokine signaling and the activation of the UPRmt response in the intestine of these mutants. During his sabbatical in the Dillin group, Dr. Arriaga proposes to use his bioanalytical expertise and experience in subcellular analysis of ROS to investigate the association that exists between ROS and mitokines. Dr. Dillin, who is a leader in the use of C. elegans for genetic and age-related studies, will provide a highly suited experimental and intellectual environment to complete the proposed work and train Dr. Arriaga in the use of C. elegans as a model organism of aging. The specific aims of the F33 application are: (1) Introduce Dr. Arriaga to C. elegans research during his sabbatical at the Dillin lab; (2) determine the role of mitochondrial ROS in signaling from neurons to intestine in ETC-deficient C. elegans. In addition to moving toward the characterization of mitokines, completion of the proposed work will (1) establish a highly-complementary collaboration between the Dillin and Arriaga groups, (2) introduce new bioanalytical resources to the Dillin Group, and (3) train Dr. Arriaga on the use of C. elegans to provide a new direction to complement Dr. Arriaga's age-related studies. Health relevance: There is compelling evidence that the longevity pathways in C. elegans are conserved in other more complex organisms including mammals. Thus, the findings of this research contribute to the understanding on how mitochondrial deficiencies in one tissue may activate stress responses in other tissue, which are extremely relevant to aging and age-related diseases. PUBLIC HEALTH RELEVANCE: Narrative Mitochondria deficiencies in the neurons of C. elegans activate a stress response in the intestine that is implicated in longevity. Stress responses are extremely relevant to aging and age-related diseases in humans.